Functionalization of diazines and benzo derivatives ...szolcsanyi/education/files/Chemia... · Functionalization of diazines and benzo derivatives through deprotonated intermediates

Functionalization of diazines and benzo derivatives through deprotonatedintermediates

Floris Chevallier and Florence Mongin*

Received 23rd October 2007

First published as an Advance Article on the web 20th November 2007

DOI: 10.1039/b709416g

This critical review targets as a readership researchers generally oriented toward organic synthesis

and in particular those active in heterocyclic chemistry. Diazines and benzo derivatives can

undergo deprotonative metalation provided that the base is properly chosen. Metalation reactions

of a large range of substrates can be performed using hindered lithium dialkylamides such as

lithium 2,2,6,6-tetramethylpiperidide. Subsequent reactions with electrophiles open an entry to a

great variety of building blocks, notably for the synthesis of biologically active compounds. (83

references)

1. Introduction

Diazines belong to the most important heterocycles containing

nitrogen. Many natural products are derived from pyrimidine.

Thymine, cytosine and uracil are for example important as

building blocks for the nucleic acids, orotic acid is the key

compound in the biosynthesis of almost all naturally occurring

pyrimidine derivatives, and aneurin (thiamine, vitamin B1) is

present in yeast, in rice polishing and in various cereals. A few

pyrimidine antibiotics possess potent antitumor properties

(e.g. bleomycin). Several natural products contain the quinazo-

line structure; examples are the quinazoline alkaloids isolated

from rutaceae (e.g., arborine). In addition, the pyrimidine core

is present in many pharmaceuticals such as trimethoprim,

sulfadiazine, pyrimethamine, hexetidine, 5-fluorouracil and

zidovudin, as well as in herbicides (e.g., bensulfuronmethyl),

and the quinazoline ring occurs in pharmaceuticals such as

methaqualone, quinethazone, proquazone and prazosin.1

Few natural compounds contain the pyridazine ring.

Derivatives such as pyrazon and pyridaben show biological

activity and are applied as herbicides and anthelmintics. In

contrast, pyrazines occur frequently as flavor constituents in

foodstuffs that undergo heating (coffee, meat...).

Alkylpyrazines also act as ant pheromones. Since a high

degree of structural complexity characterizes such compounds,

there is a need for highly selective, flexible and efficient

synthetic methods.1

Pyridazines can be prepared using one of the following

approaches: (1) cyclocondensation reactions between 1,4-

dicarbonyl compounds and hydrazine, (2) cyclocondensation

reactions between 1,2-diketones, reactive a-methylene esters

and hydrazine2 and (3) cycloaddition/cycloreversion

sequences.3 Bare pyridazine is produced from maleic anhy-

dride: reaction of the latter with hydrazine yields maleic

hydrazide which, upon treatment with POCl3/PCl5, affords

3,6-dichloropyridazine, a precursor of pyridazine (reductive

dehalogenation using catalytic hydrogenation). Cinnolines can

be generated by intramolecular cyclization of o-alkenyl or

o-alkynyl aryldiazonium salts, and phthalazines by cyclocon-

densation of o-diacylbenzenes with hydrazine.1

Synthese et Electrosynthese Organiques, Universite de Rennes 1, CNRS,Batiment 10A, Case 1003, Campus scientifique de Beaulieu, F-35042Rennes, France. E-mail: [email protected];Fax: +33-2-23-23-69-55

Floris Chevallier was born inFrance in 1978 and received hisPhD from the University ofNantes in 2004 with ProfessorJean-Paul Quintard (organotinchemistry). He then moved tothe University of Freiburg imBreisgau as a postdoctoral fel-low with Professor BernhardBreit (catalysis and supramole-cular chemistry). He is cur-rently working with ProfessorFlorence Mongin at theUniversity of Rennes 1. Hisresearch interests include themethodological study of ’ate

complexes as deprotonating agents and its applications to thesynthesis of bioactive heterocyclic molecules.

Florence Mongin obtained herPhD in chemistry in 1994 fromthe University of Rouen underthe supervision of Prof. GuyQueguiner. After a two yearstay at the Institute of OrganicChemistry of Lausanne as apost-doctoral fellow with Prof.Manfred Schlosser, she returnedto the University of Rouen as anAssistant Professor in 1997(habilitation in 2003). She tookup her present position in 2005as Professor at the University ofRennes. Her scientific interestsinclude heterocyclic chemistry,

particularly the use of organometallic compounds to deprotonatearomatics.

Floris Chevallier Florence Mongin

CRITICAL REVIEW www.rsc.org/csr | Chemical Society Reviews

This journal is � The Royal Society of Chemistry 2008 Chem. Soc. Rev., 2008, 37, 595–609 | 595

Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03

. View Article Online / Journal Homepage / Table of Contents for this issue

http://dx.doi.org/10.1039/b709416g

http://pubs.rsc.org/en/journals/journal/CS

http://pubs.rsc.org/en/journals/journal/CS?issueid=CS037003

Pyrimidines are mainly synthesized by cyclocondensation

reactions of 1,3-dicarbonyl compounds (or other 1,3-bis-

electrophiles) with amidines, ureas, thioureas, guanidines and

urethanes.4 Phosphazenes containing an amidine moiety can

be converted to pyrimidines by reaction with a,b-unsaturated

aldehydes (aza-Wittig reaction) followed by oxidative electro-

cyclic ring closure.5 Condensation of 1,1,3,3-tetraethoxypro-

pane with formamide furnishes bare pyrimidine.6 Several

methods exist to access to quinazolines.1

Pyrazines are generally produced by self-condensation of

a-amino carbonyl compounds and the combination of

a-diketones with vicinal diamines followed by dehydrogena-

tion,7 but these methods disappoint in the preparation of

unsymmetrically substituted pyrazines. Alternative syntheses

include cyclizing aza-Wittig reactions of two molecules of

a-phosphazinyl ketones or oxidation of dioxopiperazines. Few

regioselective syntheses exist.8 Similar approaches are

described to reach quinoxalines.1

The reactions of diazines are determined by the presence of

the ring N atoms. The latter are attacked by electrophiles, but

deactivate the ring C atoms. Hence, few SEAr processes take

place, and if so, in moderate yields. Diazines are more reactive

than pyridine towards nucleophiles (addition and substitution

reactions). Concerning benzodiazines, SEAr reactions take

place, when possible, on the benzene ring, whereas nucleophilic

substitutions occur in the diazine ring, particularly if

substituted by halogens.1

Site selectivity could be easily achieved of course if the

electrophile could react with a specific diazinylmetal rather

than with the unmodified heterocycle. Non-deprotonative

accesses to diazinylmetals such as halogen–metal exchange

have been developed,9 but the problem is only deferred since

the preparation of bromo- and polybromodiazines that could

be used as substrates is generally not trivial. The metalation

(hydrogen–metal permutation) avoids the use of heavy

halogen-substituted diazines.

The acidities of hydrogens in diazines are related to the less

highly-conjugated p orbitals (decrease in aromaticity) in the

ring when compared to azines (and of course benzene). The

pKa values for C–H bonds of numerous aromatic heterocyclic

compounds including diazines have been recently calculated.10

The strongest acidity on diazines was estimated to be the

4-position of pyridazine (31.1), and the weakest one the

2-position of pyrimidine (40.0) (Scheme 1).

Unlike five-membered heterocycles, for which protons

adjacent to heteroatom have the strongest acidity, six-

membered heterocycles have the weakest acidic protons

adjacent to nitrogens, a result of the more important repulsion

between the lone electron pair of nitrogen and the negative

charge of the carbanion for the latter, due to the smaller angle

between the two electron clouds.10

As a consequence, using the nonmetallic tBu-P4 organic

base (pKa = 42.7 in MeCN), which is highly chemoselective

and proceeds without coordination to ring nitrogen, pyrida-

zine and pyrimidine are regioselectively deprotonated at the

most acidic 4- and 5-positions, respectively, as evidenced by

trapping by a carbonylated compound (Scheme 2).11

When metallic bases are employed to deprotonate

p-deficient aza-heterocycles, the regioselectivity of the reaction

is generally different because of additional effects.12

Coordination of the/a ring nitrogen to the metal (particularly

in the absence of a chelating solvent such as THF) causes the

disaggregation of the base (which becomes more reactive),

increases the electron-withdrawing effect of the nitrogen, and

(thus) favors the deprotonation at an adjacent position. Since

diazines (pyridazine: pKa = 2.3, pyrimidine: pKa = 1.3,

pyrazine: pKa = 0.4) are less basic than pyridine (pKa = 5.2),

this effect is supposed to be less important. In addition, it

should be noted that the compound lithiated at the nitrogen

adjacent position is on the one hand stabilized by the electron-

withdrawing effect of the nitrogen(s), but on the other hand

destabilized by electronic repulsion between the carbanion and

the lone pair of the adjacent nitrogen.

The electron-withdrawing effect of the diazine nitrogens

decreases the energy level of the LUMO of these substrates

and makes them more sensitive to nucleophilic addition.12a,13

As a consequence, ‘‘soft’’ alkyllithiums, which are strong bases

(pKa y 40–50), have to be avoided since they easily add

nucleophilically to the diazine ring, even at low temperatures.

It is advisable to rely upon the ‘‘harder’’, though less basic

lithium diisopropylamide (LDA, pKa = 35.7) and lithium

2,2,6,6-tetramethylpiperidide (LTMP, pKa = 37.3) to effect

deprotonation. Nevertheless, this still happens to be difficult

with bare heterocycles, for which formation of dimeric

products – either by addition of lithiated substrate to anotherScheme 1 Estimated pKa values for C–H bonds.

Scheme 2 Deprotonative functionalization of pyridazine and pyrimi-

dine using tBu-P4 base. Reaction conditions: [a] tBuCHO, tBu-P4, ZnI2,

toluene, 275 uC to rt; [b] tBuCHO, tBu-P4, ZnI2, toluene, 275 uC to rt.

596 | Chem. Soc. Rev., 2008, 37, 595–609 This journal is � The Royal Society of Chemistry 2008

Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03

. View Article Online


molecule14 or by dimerization of ‘‘radical anions’’ – can hardly

be avoided.15 When compared to pyridine, nitrogens of

diazines are less chelating but the ring hydrogens are

more acidic. For these reasons, reactions should be less

regioselective.

Using lithium amides as the bases, the reaction is usually

under thermodynamic control, and the regioselectivity

observed is the result of different effects such as stabilization

by the electron-withdrawing effect of the ring nitrogens and

destabilization by electronic repulsion between the carbanion

and the lone pair of the adjacent ring nitrogen. These effects

are modulated by the aggregation state of the lithium species,

which largely depends on the solvent, for example. A

rationalization of the regioselectivity becomes more compli-

cated when substituted diazines are concerned. As the ring

nitrogen, the substituent can stabilize by inductive electron-

withdrawing effect. It can also chelate the Lewis acidic metal

of the base, an effect that is important for the few reactions

carried out under kinetic control using alkyllithiums since it

allows the disaggregation of the base, reinforces the electron-

withdrawing effect of the substituent and increases the

proximity effect of the complexed base. Under thermodynamic

control, unlike the ring nitrogen the substituent can stabilize

the metalated substrate by chelation, which reinforces the

electron-withdrawing effect. Steric hindrance caused by the

substituent has an impact on the outcome of the reaction too.

Some of these effects could explain the regioselectivity

observed in the examples depicted in Scheme 3.16

2. Metalation of pyridazines, cinnolines and

phthalazines

2.1 Metalation of bare pyridazine and long range activated

cinnolines

Few attempts to deprotonate bare pyridazine have been

described in the literature. Monometalation next to nitrogen

was found possible with 4 molar equiv. of LTMP and very

short reaction times at 275 uC, a result evidenced by

interception with deuterium chloride, benzaldehyde, acetalde-

hyde or elemental iodine to give the functionalized pyridazines

1 though in 16 to 32% yields. When tert-butyldimethylsilyl

chloride was used instead, the 4-substituted pyridazine was

produced in a very low 10% yield.17 Using an in situ prepared

mixture of ZnCl2?TMEDA (0.5 equiv.) and LTMP (1.5 equiv.)

in THF containing 5 extra equiv. of TMEDA, the zincation

could be performed at reflux to give after quenching

with elemental iodine a 83 : 9 : 8 mixture of 3-iodo, 4-iodo

and 3,5-diiodopyridazine, respectively, from which the main

compound was isolated in 66% yield18 (Scheme 4).

Provided that their pyridazine ring is completely substituted,

cinnolines can be deprotonated on the benzene ring, next to

the ring nitrogen (Scheme 5).19 Interception with iodine

allowed subsequent arylation through Suzuki or Stille

cross-couplings.

In general, the substituents help in steering the metal to the

targeted location.

2.2 Metalation of halo- pyridazines, cinnolines and phthalazines

Metalation of 3-bromo-6-phenylpyridazine was achieved using

a twofold excess of LDA in THF at 2100 uC. The complete

regioselectivity next to the bromo group was inferred by

trapping the lithio compound with 4-anisaldehyde (84%

yield).20

Starting from 3,6-dichloropyridazine, the LTMP-mediated

deprotonation proceeded in THF at 270 uC, and led to the

4-substituted derivatives 2 in variable yields after subsequent

trapping (Scheme 6).21

Replacing one of the chloro groups by another sub-

stituent offered challenging model compounds to test the

Scheme 3 Deprotonative functionalization of (2-pyridyl)pyrazine

and 3-phenyl-6-(2-pyridyl)pyridazine. Reaction conditions: [a] LTMP,

THF, 2100 uC, 15 min; [b] Electrophile: Bu3SnCl; [c] LTMP, THF,

278 uC, 15 min; [d] Electrophile: 4-MeOC6H4CHO; [e] hydrolysis.

Scheme 4 Deprotonative functionalization of pyridazine. Reaction

conditions: [a] LTMP, THF, 275 uC, 6 min; [b] Electrophile {El}: DCl

{D}, PhCHO {CH(OH)Ph}, MeCHO {CH(OH)Me}, I2 {I}; [c]

hydrolysis; [d] ZnCl2?TMEDA, LTMP, TMEDA, THF, reflux, 2 h;

[e] Electrophile: I2.

Scheme 5 Deprotonative functionalization of 4-chloro-3-methoxy-,

4-(4-methoxyphenyl)-3-trimethylsilyl- and 4-(4-trifluoromethylphe-

nyl)-3-trimethylsilylcinnoline. Reaction conditions: [a] LTMP, THF,

275 uC, 30 min to 1 h; [b] Electrophile: I2.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



regioselectivity of the reaction. With 3-chloro-6-fluoropyrida-

zine, metalation using either LDA or LTMP in THF at low

temperature took place next to the smaller halogen.22 With a

pivaloylamino group instead, reaction using LTMP in THF at

270 uC occurred randomly whereas employing LDA (4 equiv.)

exclusively afforded deprotonation at the position adjacent to

the halogen, providing after trapping with acetaldehyde or

benzaldehyde the expected alcohols in 68–82% yields.23

The situation became more complex with 3-chloro-6-

methoxypyridazine. The 4- (next to the chloro group) and

5- (next to the methoxy group) substituted derivatives were

produced in a 20 : 80 ratio after reaction with LTMP in THF

at 270 uC followed by trapping with iodomethane.24 Recourse

to very hindered bases such as lithium N-tert-butyl-N-(1-

isopropylpentyl)amide (LB1) allowed a 1 : 99 ratio to be

reached using the same electrophile.25 It was noted that using

the in situ trapping method metalation also occurred regio-

selectively next to the methoxy group.26

When one of the chloro groups was replaced with a

methoxyethoxy, using LDA or LTMP in THF at 270 uCgave a mixture of both possible lithio compouds23 (Scheme 7).

Functionalization of 3- and 4-chlorocinnoline at the vacant

4- and 3-position, respectively, was achieved in satisfying yields

through deprotonation using LTMP in THF at low tempera-

tures, to furnish the compounds 3 and 4, respectively

(Scheme 8).19a

Butyllithium surprisingly gave better results than LTMP

when used to functionalize 6-chloro-1,4-dimethoxyphthala-

zine. Metalation solely occurred at the 7-position, leading to

the compounds 5. In the absence of chloro group, the addition

product 6 was formed instead (Scheme 9).27

2.3 Metalation of alkoxy- pyridazines and cinnolines

When subsequently treated with LTMP in THF at 270 uC and

electrophiles, 3,6-dimethoxypyridazine was converted to the

4-substituted derivatives 7. Good yields were obtained when

benzaldehyde, iodomethane, chlorotrimethylsilane and tosyl

azide were chosen to trap the lithio intermediate (Scheme 10).28

In contrast, the low conversion observed quenching the

reaction mixture with DCl tends to show that metalation still

takes place after the introduction of the electrophiles, by

equilibrium shift.13c Alternatively, butyllithium can be used to

bring about the deprotonation step.29

Starting from 3-(methoxyethoxy)pyridazine, only low yields

(12–15%) of 4-substituted derivatives were obtained after

treatment with LTMP (2 equiv.) in THF at 270 uC and

subsequent quenching with acetaldehyde or benzaldehyde.23

Scheme 6 Deprotonative functionalization of 3,6-dichloropyridazine.

Reaction conditions: [a] LTMP, THF, 270 uC, 1.5 h; [b] Electrophile

{El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}, 4-MeOC6-

H4CHO {CH(OH)(4-MeOC6H4)}, 2-MeOC6H4CHO {CH(OH)(2-

MeOC6H4)}, PhCONMe2 {COPh)}, Me3SiCl {SiMe3}, HCONMe2

{CHO}, Ph2CO {C(OH)Ph2}, I2 {I}; [c] hydrolysis.

Scheme 7 Regioselectivity of the metalation of 3-chloro-6-fluoro-

pyrid-azine, N-pivaloyl protected 3-amino-6-chloropyridazine,

3-chloro-6-meth-oxypyridazine and 3-chloro-6-(methoxyethoxy)pyri-

dazine using hindered lithium amides.

Scheme 8 Deprotonative functionalization of 3- and 4-chlorocinno-

line. Reaction conditions: [a] LTMP, THF, 275 uC, 2 h; [b] Electrophile

{El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}; [c] hydrolysis;

[d] LDA, THF, 275 uC, 30 min; [e] Electrophile {El}: MeCHO

{CH(OH)Me}, PhCHO {CH(OH)Ph}, 4-MeOC6H4CHO

{CH(OH)(4-MeOC6H4)}, MeI {Me}, I2 {I}, CO2 {CO2H}.

Scheme 9 Deprotonative functionalization of 6-chloro-1,4-dimethoxy-

phthalazine. Reaction conditions: [a] BuLi, THF, 275 uC, 30 min; [b]

Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}, MeI

{Me}, I2 {I}; [c] hydrolysis.

Scheme 10 Deprotonative functionalization of 3,6-dimethoxypyrida-

zine. Reaction conditions: [a] LTMP, THF, 270 uC, 15 min; [b]

Electrophile {El}: PhCHO {CH(OH)Ph}, MeI {Me}, Me3SiCl

{SiMe3}, TsN3 {N3}; [c] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



The metalation of 3- and 4-methoxycinnolines was achieved

under similar conditions. Starting from 4-methoxycinnoline,

the 3-substituted derivatives 8 were obtained in good yields

when 2 equiv. of LDA were used. Complications were

encountered with 3-methoxycinnoline since both the 4-sub-

stituted derivatives 9 and the 4,8-disubstituted derivatives were

obtained after reaction with 2 equiv. of LTMP followed by

trapping with chlorotrimethylsilane (74 and 14%, respectively)

or elemental iodine (73 and 22%) (Scheme 11).19a

2.4 Metalation of sulfanyl-, sulfinyl- and sulfonyl- pyridazines

and cinnolines

Studies have been performed in order to compare the ability to

direct the metalation of the methoxy group with sulfanyl,

sulfinyl and sulfonyl groups. It emerged from the results that

the phenylsulfinyl and phenylsulfonyl groups are able to

compete with the methoxy group to orient the reaction on the

neighboring site using LTMP in THF at 275 uC.30

Comparable results were obtained with the tert-butylsulfinyl

and tert-butylsulfonyl groups.31 A sulfonamide group was also

compared to a chloro group with the help of a 3,6-

disubstituted pyridazine, and proved to be the more able to

direct the reaction (Scheme 12).

Chiral sulfoxides have been used to direct deprotonation

reactions of diazines. In the case of 3,6-dimethoxy-4-(4-

tolylsulfinyl)pyridazine, metalation using LTMP (3 equiv.) in

THF at 275 uC followed by trapping with various aldehydes

to afford the compounds 10 proceeded with high diastereo-

selectivity.32 When the tosylimine of benzaldehyde was used as

an electrophile, the cyclic sulfenamide 11 was isolated instead

of the expected adduct, probably through 1,2-elimination or

[2,3] sigmatropic process leading to isobutene and a sulfenic

acid, whose amino group attacks the electrophilic sulfenic acid

before elimination of water33 (Scheme 13).

The sensitivity of the sulfoxide group to nucleophilic

addition prevented clean deprotonation reactions from taking

place when present at the 4-position of cinnoline. In contrast,

3-tert-butyl- and 3-(4-tolyl)sulfinylcinnoline were metalated

with success (2 equiv. of base) to furnish the compounds 12–

13, and a diastereoisomeric excess was observed (Scheme 14).34

2.5 Metalation of N-monoprotected aminopyridazines

The metalation of N-pivaloyl protected 3-aminopyridazine

occurred on treatment with 4 equiv. of LTMP in THF at

270 uC, as evidenced by trapping with aldehydes to give the

derivatives 14. N-tert-butoxycarbonyl protected 3-aminopyr-

idazine was similarly deprotonated; the compound 15 was

isolated after reaction with aldehydes and subsequent cycliza-

tion during the work-up (Scheme 15).23

With N-pivaloyl and N-tert-butoxycarbonyl protected

4-aminopyridazine, reaction with LTMP in THF at 270 uCexclusively occurred at the 5-position. This was evidenced by

Scheme 11 Deprotonative functionalization of 4- and 3-methoxycin-

noline. Reaction conditions: [a] LDA, THF, 275 uC, 30 min; [b]

Electrophile {El}: PhCHO {CH(OH)Ph}, HCO2Et {CHO}, I2 {I}; [c]

hydrolysis; [d] LTMP, THF, 275 uC, 30 min; [e] Electrophile {El}:

PhCHO {CH(OH)Ph}, Me3SiCl {SiMe3}, I2 {I}.

Scheme 12 Regioselectivity of the metalation of 6-sulfur derivatives

of 3-methoxy- and 3-chloropyridazine using LTMP in THF at 275 uC.

Scheme 13 Deprotonative functionalization of 3,6-dimethoxy-4-(4-

tolylsulfinyl)pyridazine. Reaction conditions: [a] LTMP, THF, 275 uC,

1 h; [b] Electrophile {El}: MeCHO {CH(OH)Me}, EtCHO

{CH(OH)Et}, PhCHO {CH(OH)Ph}; [c] hydrolysis.

Scheme 14 Deprotonative functionalization of 3-tert-butylsulfinyl-

and 3-phenylsulfinylcinnoline. Reaction conditions: [a] LTMP, THF,

275 uC, 1 h; [b] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, 4-MeOC6H4CHO {CH(OH)(4-MeOC6H4)}, tBuCHO

{CH(OH)tBu}, I2 {I}, Bu3SnCl {SnBu3}; [c] hydrolysis; [d] LDA,

THF, 275 uC, 30 min; [e] Electrophile {El}: DCl {D},

4-MeOC6H4CHO {CH(OH)(4-MeOC6H4)}.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



further transformation of the lithio intermediates to afford the

compounds 16 and 17, respectively (Scheme 16).35

2.6 Metalation of pyridazinecarboxamides and

pyridazinethiocarboxamides

Lithiation of N-(tert-butyl)pyridazine-4-carboxamide using

LTMP in THF at low temperature occurred regioselectively

at the 5-position, leading to the compounds 18 (Scheme 17). In

contrast, mixtures of 5- and 6-substituted derivatives were

obtained starting from N-benzylpyridazine-4-carboxamide.35

Reaction of N-(tert-butyl)pyridazine-3-carboxamide was

reported later under similar conditions. Deprotonation gen-

erally led to the 4-substituted derivatives 19, except with

elemental iodine for which a halogen migration occurred

(compound 20), probably promoted by the excess of base

(4 equiv. were used) during the trapping step. Turning to the

corresponding thiocarboxamide modified the regioselectivity

in favor of the 5-position. This opened an entry to the

5-substituted derivatives 21 though in moderate yields,

probably in relation with the absence of stabilization of the

lithio derivative by chelation (Scheme 18). It was noted that

when a methylsulfanyl group was located at the 6-position of

N-(tert-butyl)pyridazine-3-carboxamide, reaction took place in

its vicinity using LDA.36

3. Metalation of pyrimidines and quinazolines

3.1 Metalation of bare pyrimidine and long range activated

pyrimidines and quinazolines

Alkyldiazines are in general prone to lateral metalation.

5-Methylpyrimidine is an exception since it was deprotonated

at the 4-position on treatment with LDA, a result evidenced by

trapping with benzophenone.14 This is the first pyrimidine

metalation.

The reaction of bare pyrimidine with LTMP is not very

tempting from a synthesis point of view. When attempted at

various temperatures in THF or DEE, only small amounts of

substrate and 4,49-dimer 22 were identified, due to the

instability of the lithio compound under the conditions

applied. The compatibility of hindered lithium amides

with some electrophiles allowed the in situ quenching of

the 4-lithio compound to furnish the derivatives 23 though the

4,6-disubstituted product 24 was produced together using

benzophenone (Scheme 19).17

Combining LTMP (1.5 equiv.) with ZnCl2?TMEDA

(0.5 equiv.) in THF at 25 uC, the 4-metalated compound

could be accumulated to give, after trapping, the products 25

(Scheme 20).18

With a methoxy group located at the 2-position, the 4-lithio

derivative could be accumulated using 4 equiv. of LTMP

(albeit a short reaction time has to be used) owing to an

increase of the acidity of the hydrogens and a stabilization by

Scheme 15 Deprotonative functionalization of N-pivaloyl and

N-tert-butoxycarbonyl protected 3-aminopyridazine. Reaction condi-

tions: [a] LTMP, THF, 270 uC; [b] Electrophile {R9}: MeCHO {Me},

PhCHO {Ph}; [c] hydrolysis.

Scheme 16 Deprotonative functionalization of N-pivaloyl and

N-tert-butoxycarbonyl protected 4-aminopyridazine. Reaction condi-

tions: [a] LTMP, THF, 270 uC, 2.5 h; [b] Electrophile {R9}: MeCHO

{Me}, PhCHO {Ph}; [c] hydrolysis.

Scheme 17 Deprotonative functionalization of N-(tert-butyl)pyrida-

zine-4-carboxamide. Reaction conditions: [a] LTMP, THF, 275 uC,

15 min to 2 h; [b] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, Me3SiCl {SiMe3}; [c] hydrolysis.

Scheme 18 Deprotonative functionalization of N-(tert-butyl)pyrida-

zine-3-carboxamide. Reaction conditions: [a] LTMP, THF, 275 uC, 1 h;

[b] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph},

I2 {I}; [c] hydrolysis; [d] Electrophile {El}: MeCHO {CH(OH)Me},

PhCHO {CH(OH)Ph}, Ph2CO {C(OH)Ph2}, Bu3SnCl {SnBu3}, MeI

{Me}, I2 {I}, C2Cl6 {Cl}.

Scheme 19 Deprotonative functionalization of pyrimidine using the

in situ trapping technique. Reaction conditions: [a] LTMP, THF,

270 uC, Electrophile {El}: Me3SiCl {SiMe3}, PhCHO {CH(OH)Ph},

Ph2CO {C(OH)Ph2}; [b] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



electron-withdrawing effect. The 4-functionalized derivatives

26 were isolated in moderate yields after trapping with ‘‘hard’’

electrophiles such as deuterium chloride (56%), benzaldehyde

(29%), acetaldehyde (26%) or 2,3,4-trimethoxybenzaldehyde

(28%). Using electrophiles more compatible with lithium

amides, the formation of 4,6-disubstituted pyrimidines 27

(41% using chlorotrimethylsilane and 25% using phenyl

disulfide) and even 4,5,6-trisubstituted pyrimidines 28 (7%

using elemental iodine) could not be avoided (Scheme 21).

Similar results have been observed starting from 2-(4-

methoxyphenyl)pyrimidine.17

With a chloro group located at the 2-position, the

accumulation of a 4-metalated derivative proved unsatisfac-

tory using LTMP.17 Nevertheless, using the mixed Mg/Li

amide TMPMgCl?LiCl (1 equiv.), it became possible when

used in THF at temperatures between 255 and 240 uC, as

demonstrated by interception with electrophiles to furnish the

4-functionalized derivatives 29 (Scheme 22).37

Owing to the substituent at the 2-position, which avoids a

nucleophilic attack of the base at this position, 2-tert-butyl-

4(3H)-quinazolinone was lithiated on the benzene moiety upon

treatment with TMEDA-chelated sec-butyllithium (4 equiv.) at

220 uC, regioselectively leading to the 5-substituted derivatives

30 (Scheme 23).38 5-Aryl derivatives were then prepared by

coupling from compounds 30 (El = B(OH)2).

3.2 Metalation of halopyrimidines

In the bromodiazine series, the success of the metalation

depends closely on the reaction conditions. When a mixture of

5-bromopyrimidine and a carbonyl compound was treated by

LDA (1 equiv.) in DEE at 2100 uC for 2 h, the 4-substituted

5-bromopyrimidines 31 were obtained after hydrolysis in

moderate yields. In the absence of electrophile, the dihydro-

pyrimidylpyrimidine 32 was isolated after hydrolysis in 32%

yield (Scheme 24).39 Accumulation of a 4-metalated 5-bromo-

pyrimidine proved possible using the mixed Mg/Li amide

TMPMgCl?LiCl in THF at temperatures between 255 and

240 uC.37

Starting from 2,4-dibromopyrimidine, lithio compounds

could be accumulated at 2100 uC using 3 equiv. of LDA or

more hindered and basic LTMP. The 5-lithio derivative was

mainly generated using the former and the 6-lithio using the

latter. This was shown by interception with acetaldehyde or

4-methoxybenzaldehyde (20–26% of 33 and 2–5% of 34 using

LDA, and 21–24% of 34 and 0–8% of 33 using LTMP)

(Scheme 25).20

Scheme 20 Deprotonative functionalization of pyrimidine using a

mixed Li/Zn amide. Reaction conditions: [a] ZnCl2?TMEDA, LTMP,

THF, 25 uC, 2 h; [b] Electrophile {El}: I2 {I}, ClPPh2 {PPh2}.

Scheme 21 Deprotonative functionalization of 2-methoxypyrimidine.

Reaction conditions: [a] LTMP, THF, 275 uC, 5 min; [b] Electrophile

{El}: DCl {D}, PhCHO {CH(OH)Ph}, MeCHO {CH(OH)Me}, 2,3,4-

tri(MeO)C6H2CHO {CH(OH)(2,3,4-tri(MeO)C6H2)}, Me3SiCl

{SiMe3}, (PhS)2 {SPh}, I2 {I}; [c] hydrolysis.

Scheme 22 Deprotonative functionalization of 2-chloropyrimidine.

Reaction conditions: [a] TMPMgCl?LiCl, THF, 255 to 240 uC, 2 h; [b]

Electrophile {El}: MeSSO2Me {SMe}, 4-BrC6H4CHO {CH(OH)(4-

BrC6H4)}; [c] hydrolysis.

Scheme 23 Deprotonative functionalization of 2-tert-butyl-4(3H)-

quinazolinone. Reaction conditions: [a] sBuLi, TMEDA, THF,

220 uC, 1 h; [b] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, (PhS)2 {SPh}, Bu3SnCl {SnBu3}, I2 {I}, B(OMe)3

{B(OH)2}; [c] hydrolysis.

Scheme 24 Deprotonative functionalization of 5-bromopyrimidine

using the in situ trapping technique. Reaction conditions: [a] LDA,

DEE, 2100 uC, Electrophile {El}: 4-FC6H4C(O)(2-ClC6H4) {COH(4-

FC6H4)(2-ClC6H4)}, 4-ClC6H4C(O)iPr {COH(4-ClC6H4)(iPr)},

PhCHO {CH(OH)Ph}; [b] hydrolysis.

Scheme 25 Deprotonative functionalization of 2,4-dibromopyrimi-

dine. Reaction conditions: [a] LDA or LTMP, THF, 2100 uC, 30 min;

[b] Electrophile {R}: MeCHO {Me}, 4-MeOC6H4CHO {CH(OH)(4-

MeOC6H4)}; [c] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



When the corresponding dichloropyrimidine was treated

with LTMP, the regioselectivity of the reaction proved to be

dependent on the reaction conditions. 1 : 1 Mixtures of 5- and

6-substituted derivatives were obtained when the substrate was

successively treated with LTMP in THF at 270 uC and an

electrophile. The 5-lithio compound was generated in a THF–

DEE mixture at 2100 uC whereas the 6-lithio was formed in a

THF–HMPA mixture at 270 uC; trapping with acetaldehyde

afforded the corresponding alcohols 35 and 36 in 11 and 18%

yield, respectively (Scheme 26).21

Using LDA in THF at 280 uC resulted in the regioselective

formation of the 5-lithio derivative, as demonstrating by

trapping with benzaldehyde or chlorotrimethylsilane to furnish

the compounds 37 in low yields. The derivatives 38 and 39

were analogously accessed from the 5-lithio compounds of

4,6-dichloro- and 2,4,6-trichloropyrimidine, benefiting from

doubly activated positions (Scheme 27). Butyllithium could

also be used for the deprotonation of 4,6-dichloro- and 2,4,6-

trichloropyrimidine, but the expected alcohols were given in

lower yields after trapping with benzaldehydes.40

A similar problem of regioselectivity arose in the case of

2,4-dichloropyrimidine and 2-(methylsulfanyl)-4-chloropyri-

midine. Whereas LDA in THF at 270 uC mainly metalated

both substrates at the 5-position next to the chloro group (9 : 1

and 19 : 1 ratio, respectively, when aldehydes were used to trap

the lithio intermediates), LTMP concomitantly attacked the

hydrogen next to the ring nitrogen (1 : 1 and 1 : 2 ratio,

respectively). Surprisingly, when elemental iodine was used to

trap the mixture of lithio compounds generated with LDA or

LTMP from 2-(methylsulfanyl)-4-chloropyrimidine, only the

6-iodo derivative was obtained; this result could be due to a

quick TMP-promoted isomerization of the 5-iodo derivative

during the trapping step.41 Conversion of the 6-iodo derivative

to 6-aryl-4-chloro-2-(methylsulfanyl)pyrimidine-5-carboni-

triles endowed with antileishmanial activities, was performed

using cross-coupling with phenylboronic acid or 3-anisylzinc

chloride, and subsequent lithiation at the 5 position as key

steps.

4-Chloro-2,6-dimethoxypyrimidine was converted into the

5-lithio derivative using either LTMP to give the compounds

4042 or butyllithium to afford the compound 41.25b,43 Better

yields were obtained using the former (Scheme 28).

2,4-Difluoro- and 4-fluoro-2-(methylsulfanyl)pyrimidine

regioselectively underwent LDA-promoted metalation at the

5-position in THF at 275 uC to give the trisubstituted

compounds 42 after electrophilic trapping (Scheme 29).44

Halogenated and dihalogenated 2- or 4-(trifluoromethyl)-

pyrimidine were similarly amenable to deprotonation at the

5-position using LDA in THF at 275 uC.15

Conversely, LTMP in THF at 2100 uC was found to

deprotonate 2-(methylsulfanyl)-4-trifluoromethylpyrimidine

regioselectively next to nitrogen, leading to the 6-substituted

derivatives 43. The 4,49-dimer 44 ranked among the most

abundant by-products.45 4-Iodo-2-(methylsulfanyl)pyrimidine

behaved similarly. It was converted to the 6-lithio derivative

when treated with a very hindered base in THF at 2100 uC for

10 min, affording the compounds 4546 (Scheme 30).

3.3 Metalation of alkoxy- pyrimidines and quinazolines

Unlike 2,4-dihalopyrimidines, 2,4-dimethoxypyrimidine was

regioselectively metalated at the methoxy-adjacent position

Scheme 26 Deprotonative functionalization of 2,4-dichloropyrimi-

dine. Reaction conditions: [a] LTMP; [b] Electrophile: MeCHO; [c]

hydrolysis.

Scheme 27 Deprotonative functionalization of 2,4-dichloro-, 4,6-

dichloro- and 2,4,6-trichloropyrimidine. Reaction conditions: [a]

LDA, THF, 280 uC, 30 min; [b] Electrophile {El}: PhCHO

{CH(OH)Ph}, Me3SiCl {SiMe3}; [c] hydrolysis.

Scheme 28 Deprotonative functionalization of 4-chloro-2,6-

dimethoxypyrimidine. Reaction conditions: [a] LTMP, THF, 225 uC,

1 h; [b] Electrophile {El}: DCl/EtOD {D}, MeCHO {CH(OH)Me},

PhCHO {CH(OH)Ph}, 2-MeOC6H4CHO {CH(OH)(2-MeOC6H4)},

3,4,5-tri(MeO)C6H2CHO {CH(OH)(3,4,5-tri(MeO)C6H2)}, HCO2Et

{CHO}, I2 {I}, Me3SnCl {SnMe3}; [c] hydrolysis; [d] BuLi, THF,

275 uC, 10 min; [e] Electrophile {El}: TsN3 {N3}.

Scheme 29 Deprotonative functionalization of 2,4-difluoro- and

4-fluoro-2-(methylsulfanyl)pyrimidine. Reaction conditions: [a] LDA,

THF, 275 uC, 30 min; [b] Electrophile {El}: MeCHO {CH(OH)Me},

PhCHO {CH(OH)Ph}, 2-MeOC6H4CHO {CH(OH)(2-MeOC6H4)},

2,4-diClC6H3CHO {CH(OH)(2,4-diClC6H3)}, 3,4,5-tri(MeO)C6H2-

CHO {CH(OH)(3,4,5-tri(MeO)C6H2)}, I2 {I}, HCO2Et {CHO}, CO2

{CO2H}; [c] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



when treated with LTMP in DEE at 0 uC. This was shown by

trapping the lithio compounds with aldehydes, carbon dioxide,

dimethylformamide, ethyl chloroformiate or chloro-trimethyl-

silane in yields ranging from 4 to 65%.47 These deprotonation

conditions were also applied to functionalize a series of

pyrimidines including N-pivaloyl protected 4-aminopyrimidine

(chlorotrimethylsilane quench) in low yields.

5-Methoxy, 2,4-dimethoxy (or 2,4-dibenzyloxy), 4,6-

dimethoxy and 2,4,6-trimethoxypyrimidine were all lithiated

next to the methoxy (or benzyloxy) group using LTMP in

THF at 278 uC for 15 min, leading to substituted derivatives

46–48 in medium to high yields, depending on the ability of the

electrophile to coexist with the base long enough to allow

equilibrium shift of the deprotonation reaction

(Scheme 31).25b,28

Similar results were obtained starting from 2-chloro-4-

methoxypyrimidine, allowing the synthesis of the 5-substituted

derivatives 49. Trapping with elemental iodine only furnished

the expected 5-iodo derivative 50 when the reaction was

performed at 2100 uC. At 275 uC, 2-chloro-6-iodo-4-

methoxypyrimidine 51 was formed instead, as previously

noted with 2-(methylsulfanyl)-4-chloropyrimidine

(Scheme 32).48

Metalation of the benzene ring of 4-substituted quinazoline

was more easily observed when substituents can orient the

deprotonation. Thus, metalation of 4-anilino-,27 4-(4-methoxy-

phenyl)-,19b and 4-(4-trifluoromethylphenyl)-6,7-dimethoxy-

quinazoline19b using 4–5 equiv. of lithium amide in THF at

275 uC affected the 8-position. A similar result was noted

when 6,7-dimethoxyquinazolinone was successively subjected

to the reaction with 1 equiv. of butyllithium and 4 equiv. of

LTMP. Functionalization of the lithio intermediates furnished

the compounds 52–55, respectively. 7-Chloroquinazolinone

behaved similarly (compounds 56) (Scheme 33).27,34

Compounds 53 and 54 allowed subsequent arylation through

Suzuki or Stille cross-couplings.

Scheme 30 Deprotonative functionalization of 2-(methylsulfanyl)-4-

trifluoromethyl- and 2-(methylsulfanyl)-4-iodopyrimidine. Reaction

conditions: [a] LTMP, THF, 2100 uC, 1 h; [b] Electrophile {El}:

MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}, 2-MeOC6H4CHO

{CH(OH)(2-MeOC6H4)}, 2,4-diClC6H3CHO {CH(OH)(2,4-

diClC6H3)}, 3,4,5-tri(MeO)C6H2CHO {CH(OH)(3,4,5-tri(MeO)-

C6H2)}, I2 {I}, HCO2Et {CHO}, CO2 {CO2H}; [c] hydrolysis; [d]

lithium N-tert-butyl-N-(1-isopropylpentyl)amide, THF, 2100 uC,

10 min; [e] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, Ph2CO {C(OH)Ph2}, MeI {Me}, EtI {Et}, Me3SiCl

{SiMe3}, HCO2Et {CHO}, I2 {I}.

Scheme 31 Deprotonative functionalization of 5-methoxy-, 2,4-

dimethoxy-, 4,6-dimethoxy- and 2,4,6-trimethoxypyrimidine.

Reaction conditions: [a] LTMP, THF, 278 uC, 15 min; [b]


{SiMe3}; [c] hydrolysis; [d] Electrophile {El}: PhCHO {CH(OH)Ph},

MeI {Me}, Me3SiCl {SiMe3}, PhCOCl {COPh}.

Scheme 32 Deprotonative functionalization of 2-chloro-4-methoxy-

pyrimidine. Reaction conditions: [a] LTMP, THF, 270 uC, 1 h; [b]

Electrophile {El}: DCl/EtOD {D}, MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, 2-MeOC6H4CHO {CH(OH)(2-MeOC6H4)}, 3,4,5-

tri(MeO)C6H2CHO {CH(OH)(3,4,5-tri(MeO)C6H2)}, Me3SiCl

{SiMe3}, HCO2Et {CHO}; [c] hydrolysis; [d] LTMP, THF, 2100 uC,

1 h; [e] I2.

Scheme 33 Deprotonative functionalization of 4-anilino-, 4-(4-meth-

oxyphenyl)- and 4-(4-trifluoromethylphenyl)-6,7-dimethoxyquinazo-

line, 6,7-dimethoxy- and 7-chloroquinazolinone. Reaction conditions:

[a] LTMP, THF, 275 uC, 2 h; [b] Electrophile {El}: MeCHO

{CH(OH)Me}, PhCHO {CH(OH)Ph}; [c] hydrolysis; [d] LTMP,

THF, 275 uC, 1 h; [e] Electrophile {El}: I2 {I}; [f] LDA, THF,

275 uC, 1 h; [g] BuLi, THF, 275 uC, 15 min; [h] LTMP, THF, 275 uC,

1.5 h.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



The metalation of other substituted pyrimidines has been

only scarcely examined up to now.

3.4 Metalation of N-protected aminopyrimidines

4-(tert-Butoxycarbonyl)amino-2-(trimethylsilyl)pyrimidine was

made accessible in a low 11% yield after consecutive exposures

of 4-(tert-butoxycarbonyl)aminopyrimidine to the action of

LTMP and chlorotrimethylsilane.47b This remains the sole

example of a pyrimidine deprotonation at the 2-position known

so far.

4. Metalation of pyrazines and quinoxalines

4.1 Metalation of bare and long range activated pyrazines

First mentions to a pyrazine deprotonation date from 1971,

when it was observed as a competitive reaction in nucleophilic

addition of alkyllithiums,49 and above all 1974,50 when ring

metalation was observed together with lateral metalation by

treating 2-ethyl-3-methylpyrazine with methyllithium.

As described for pyridazine, regioselective metalation of

pyrazine was found possible using 4 equiv. of LTMP and very

short exposure times at 275 uC, a result evidenced by

interception with benzaldehyde, acetaldehyde or elemental

iodine to give the functionalized pyrazines 57 in 39 to 65%

yields. When benzaldehyde was used in excess (3 equiv.), the

2,5-disubstituted pyrazine 58 was inevitably produced, prob-

ably by competitive deprotonation of the already 2-function-

alized pyrazine during the trapping step (Scheme 34).17

Using an in situ prepared mixture of ZnCl2?TMEDA

(0.5 equiv.) and LTMP (1.5 equiv.) in THF, the metalated

compound could be accumulated at room temperature to give

after trapping the monosubstituted derivatives (e.g. iodopyr-

azine in 59% yield). Starting from quinoxaline resulted in

mixtures of 2-iodo, 2,5-diiodo and 2,29-biquinoxaline under

the same reaction conditions.18

3-Chloro-a-arylpyrazine-2-methanols were deprotonated at

the 5-position upon treatment with LTMP (3 equiv.) in THF at

275 uC, leading to the derivatives 59–63 (Scheme 35).51 High

yields were obtained using a similar protocol with 2,3-

dichloropyrazine.52 Compounds 59 and 60 (El = I) were next

functionalized using a Negishi procedure as key step to furnish

septorin, the main agent of a wheat disease impeding growth.

2-Fluoro-3-phenylpyrazine was similarly deprotonated

(3 equiv. of LTMP), as demonstrated by trapping with most

of the electrophiles to afford the 6-substituted derivatives 64.

When elemental iodine was used, the 6-iodo compound 65 was

isolated only when 1 equiv. of LTMP was employed. Using

LTMP in excess (3 equiv.) and 1 equiv. of iodine, the 5-iodo

compound 66 was formed instead. The latter could result from

a deprotonation of the 6-substituted derivatives 65 with the

excess of LTMP during the quenching step with iodine,

followed by iodine migration, as depicted in Scheme 36.51b,53

4.2 Metalation of pyrazine-1-oxides

Base and solvent optimization for the deprotonation of 2,5-di-

sec-butylpyrazine-1-oxide was carried out at low temperature.

The best results were obtained using LTMP in THF in the

presence of TMEDA. The method was extended to other

substrates, affording the corresponding 2-substituted pyrazine-

1-oxides 67 in good yields (Scheme 37).54

4.3 Metalation of halo- pyrazines and quinoxalines

Bromopyrazine was deprotonated next to the bromo group

using 3 equiv. of LDA in THF at 275 uC. This was evidenced

by quenching after 15 min with acetaldehyde, benzaldehyde,

phenyl disulfide or elemental iodine to give the expected

products 68 in 62, 69, 53 and 50% yield, respectively.20

Scheme 34 Deprotonative functionalization of pyrazine. Reaction

conditions: [a] LTMP, THF, 275 uC, 6 min; [b] Electrophile {El}:

PhCHO {CH(OH)Ph}, MeCHO {CH(OH)Me}, I2 {I}; [c] hydrolysis.

Scheme 35 Deprotonative functionalization of 3-chloro- and

3-fluoro-a-arylpyrazine-2-methanols. Reaction conditions: [a] LTMP,

THF, 275 uC, 15 min; [b] Electrophile {El}: MeCHO {CH(OH)Me},

PhCHO {CH(OH)Ph}, C2Cl6 {Cl}, I2 {I}; [c] hydrolysis; [d] LTMP,

THF, 275 uC, 5 min; [e] Electrophile {El}: I2 {I}.

Scheme 36 Deprotonative functionalization of 2-fluoro-3-phenylpyr-

azine. Reaction conditions: [a] LTMP, THF, 275 uC, 5 min; [b]

Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph},

Me3SiCl {SiMe3}, Bu3SnCl {SnBu3}; [c] hydrolysis; [d] Electrophile

{El}: I2 {I}; [e] LTMP, THF, 275 uC, 30 min.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



Chloro- and iodopyrazine were similarly regioselectively

metalated, but LTMP proved to be a better base than LDA.

Due to the better stability of 2-chloro-3-lithiopyrazine, the

accumulation time could be extended to 30 min (no change

was observed using longer exposure times) to give the

3-functionalized chloropyrazines 69 in satisfying yields.55 In

contrast, the accumulation time was shortened with iodopyr-

azine in order to obtain the 3-substituted 2-iodopyrazines 70 in

satisfying yields46 (Scheme 38). The metalation next to the iodo

group was extended to a disubstituted iodopyrazine.48a

Metalation of chloropyrazines next to the halogen still

proved feasible when a substituent such as a ketal or an aryl

group was present at the 6-position.52

The metalation/functionalization sequence was applied to

2,6-dichloropyrazine to give the compounds 71 in moderate to

good yields. Nevertheless, the outcome of the reaction largely

depends on the amount of base used since the formation of 3,5-

difunctionalized products 72 could not be avoided using an

excess of metalating agent and electrophiles compatible with

in situ trapping such as benzaldehyde, elemental iodine or

chlorotributylstannane (Scheme 39).55c,56

2,6-Dichloropyrazine could serve as attractive starting

material as it offered the possibility to replace one hydrogen

by a first electrophile and the other one by a second

electrophile. The dideprotonation was optimized using

2.5 equiv. of LTMP in THF at 2100 uC, and the sequential

introduction of two different electrophiles allowed the synth-

esis of 2,6-dichloro-3,5-disubstituted compounds including 73

(Scheme 40).57

The situation becomes more complex when one has to

metalate 2-chloroquinoxaline. First attempts to use LTMP

were unsuccessful.56a The reaction was next shown to provide

the 3,39-dimer in 59% yield when DCl was used to quench the

lithio intermediate. 3-Substituted derivatives were obtained

after reaction of LTMP at 275 uC for 15–20 min and

subsequent trapping with acetaldehyde or benzaldehyde in

medium yields.58

Fluoropyrazine proved prone to proton abstraction next to

the halogen when treated with hindered lithium dialkylamides

(1 equiv.) in THF at low temperatures, LTMP giving the best

yields with a short contact time of 5 min (compounds 74).

3-Fluoro-a,a-diphenylpyrazine-2-methanol was subjected to

deprotonation too when allowed to react with LTMP at low

temperature to give the compounds 75 (Scheme 41). When the

reaction from fluoropyrazine was conducted in the presence of

Scheme 38 Deprotonative functionalization of iodo-, bromo- and

chloropyrazine. Reaction conditions: [a] LDA, THF, 275 uC, 15 min;

[b] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph},

(PhS)2 {SPh}, I2 {I}; [c] hydrolysis; [d] LTMP, THF, 270 uC, 30 min;

[e] Electrophile {El}: DCl {D}, MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, 2-furylCHO {CH(OH)(2-furyl)}, 4-MeOC6H4CHO

{CH(OH)(4-MeOC6H4)}, 2-MeOC6H4CHO {CH(OH)(2-

MeOC6H4)}, Ph2CO {C(OH)Ph2}, HCO2Et {CHO}; [f] LTMP,

THF, 275 uC, 5 min; [g] Electrophile {El}: MeCHO {CH(OH)Me},

PhCHO {CH(OH)Ph}, Ph2CO {C(OH)Ph2}, (PhS)2 {SPh}, HCO2Et

{CHO}, Me3SiCl {SiMe3}, CO2 {CO2H}, I2 {I}.

Scheme 39 Deprotonative functionalization of 2,6-dichloropyrazine.

Reaction conditions: [a] LTMP, THF, 270 uC, 2 h; [b] Electrophile

{El}: MeCHO {CH(OH)Me}, EtCHO {CH(OH)Et}, PhCHO

{CH(OH)Ph}, 2-MeOC6H4CHO {CH(OH)(2-MeOC6H4)}, 2,4-

diClC6H3CHO {CH(OH)(2,4-diClC6H3)}, HCO2Et {CHO}, I2 {I},

Me3SnCl {SnMe3}; [c] hydrolysis.

Scheme 40 Deprotonative functionalization of 2,6-dichloropyrazine.

Reaction conditions: [a] LTMP, THF, 2100 uC, 1 h; [b] First electrophile:

I2; [c] Second electrophile: 2,3,5-tri-O-benzyl-D-ribono-1,4-lactone.

Scheme 37 Deprotonative functionalization of pyrazine-1-oxides.

Reaction conditions: [a] LTMP, THF, TMEDA, 275 uC, 20 min; [b]

Electrophile {El}: HCO2Me {CHO}, 4-MeC6H4COCl {C(O)(4-

MeC6H4)}, 4-MeC6H4CO2Me {C(O)(4-MeC6H4)}; [c] Electrophile

{El}: EtCHO {CH(OH)Et}, PhCHO {CH(OH)Ph}; [d] hydrolysis;

[e] Electrophile {El}: PhCHO {CH(OH)Ph}.

Scheme 41 Deprotonative functionalization of fluoropyrazine and

3-fluoro-a,a-diphenylpyrazine-2-methanol. Reaction conditions: [a] LTMP,

THF,275 uC,5min; [b]Electrophile{El}:MeCHO{CH(OH)Me},PhCHO

{CH(OH)Ph}, Ph2CO {C(OH)Ph2}, 2-furylCHO {CH(OH)(2-furyl)},

4-MeOC6H4CHO {CH(OH)(4-MeOC6H4)}, 2-MeOC6H4CHO

{CH(OH)(2-MeOC6H4)}, HCO2Et {CHO}, (PhS)2 {SPh}, I2 {I}, BrCN

{Br}, MeCONMe2 {C(O)Me}, PhCONMe2 {COPh}; [c] hydrolysis; [d]

Electrophile {El}: Ph2CO {C(OH)Ph2}, MeCHO {CH(OH)Me}, Me3SiCl

{SiMe3}, I2 {I}, C2Cl6 {Cl}.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



an excess of base and chlorotributylstannane at 2100 uC,

2-fluoro-3,6-bis(tributylstannyl)pyrazine, which probably

results from deprotonation at C6 of intermediate 2-fluoro-3-

(tributylstannyl)pyrazine under the in situ trapping conditions

used, was isolated in 90% yield.53,59

Chloro- and fluoropyrazine were also functionalized at the

6-position using a trick. When treated with 3 equiv. of LTMP

in THF at 2100 uC in the presence of 1 equiv. of

chlorotributylstannane, the 3-(tributylstannyl) compounds 76

first formed could be converted to the 6-lithio compound

which, via migration of the tributylstannyl group, could finally

afford 2-halo-6-(tributylstannyl)pyrazines 77 after hydrolysis

(Scheme 42).52,53

Similar protocols enabled the metalation of 2-fluoro-6-

(tributylstannyl)pyrazine and 2-fluoro-6-arylpyrazines at the

3-position.53 By intercepting the lithio compounds of the latter

with iodine, subsequent Sonogashira, Negishi and Suzuki

cross-couplings proved possible. Deprotonation of 2-chloro-6-

methoxypyrazine showed incomplete regioselectivity using

LDA or LTMP in THF at 270 uC, with a 15 : 85 ratio in

favor of the 5-position next to the methoxy group.55b,c

Recourse to very hindered base lithium N-tert-butyl-N-(1-

isopropylpentyl)amide (LB1) lowered the regioselectivity at the

position adjacent to the methoxy group.22 Replacing the

chloro group with an iodo resulted in a complete regioselec-

tivity when LDA was used in THF at 270 uC.55b

When 2-fluoro-6-methoxypyrazine was allowed to react with

LDA in THF at 270 uC for 5 min, trapping with aldehydes

showed deprotonation mainly occurred next to the fluoro

group (96 : 4 ratio); LTMP and N-tert-butyl-N-(1-isopropyl-

pentyl)amide (LB1) gave lower selectivities.22

6-Chloro-2,3-dimethoxyquinoxaline features an interesting

case of regioselectivity. Treatment with LTMP (4 equiv.) in

THF for 1 h at low temperature followed by reaction with

electrophiles afforded the 5-substituted quinoxalines as major

products (85% yield using benzaldehyde as the electrophile). In

the absence of directing group on the benzene ring of

quinoxaline, e.g. with 2-methoxy-3-phenylquinoxaline, the

reaction took place at both the 5- and 8-positions.27

4.4 Metalation of alkoxy- pyrazines and quinoxalines

LTMP-promoted metalation of 2-methoxy and 2,6-dimethoxy-

pyrazine was carried out in THF at 0 uC or 275 uC to give

the compounds 78–79 after electrophilic trapping

(Scheme 43).25b,28a,29,55b,c,56,60 As previously noted for 3,6-

dimethoxypyridazine, good yields were obtained with electro-

philes sufficiently compatible with the base (1 equiv.) to allow

in situ trapping.28a This statement was confirmed by successive

treatment of 2,6-dimethoxypyrazine with LTMP (1 equiv.) at

0 uC for 15 min, and deuterated ethanol, which afforded the

3-deuterated compound in a low 32% conversion. Using

2 equiv. of base had a positive effect on the conversion (83%

after 15 min and 100% after 30 min).56b

The method using LTMP in THF at 275 uC was extended

to 2-methoxyquinoxaline (interception of the lithio compound

with N-methoxy-N-methylbenzamide in 43% yield).56a A more

complete investigation showed the yields of the 3-substituted

derivatives 80 were limited by the competitive formation of the

dimer 81 (Scheme 44).58

The dideprotonation of several pyrazine-2,5-diketals was

achieved using LTMP in THF at 225 uC for 4 h, as

demonstrated by subsequent reaction with elemental iodine

to afford the compounds 82 (Scheme 45).61 The reagent has to

be used in large excess (12 equiv.) which consumes large

amounts of the electrophile and limits the scale.

4.5 Metalation of sulfanyl-, sulfinyl- and sulfonyl- pyrazines and

quinoxalines

Methylsulfanyl- and phenylsulfanylpyrazine have been

deprotonated using LTMP in THF at 275 uC. The reaction

occurred at the 3-position, leading to the compound

83 (Scheme 46).30,56a The method was extended to

Scheme 42 Deprotonative functionalization of chloro- and fluoro-

pyrazine. Reaction conditions: [a] Bu3SnCl, LTMP, THF, 2100 uC to

240 uC, 2.5 h; [b] hydrolysis.

Scheme 43 Deprotonative functionalization of 2-methoxy- and 2,6-

dimethoxypyrazine. Reaction conditions: [a] LTMP, THF, 275 uC; [b]


{SiMe3}; [c] hydrolysis; [d] Electrophile {El}: MeCHO

{CH(OH)Me}, PhCHO {CH(OH)Ph}, PhCON(OMe)Me {COPh},

I2 {I}; [e] LTMP, THF, 0 uC, 45 min; [f] Electrophile {El}: DCl {D},

MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}, 2-MeOC6H4CHO

{CH(OH)(2-MeOC6H4)}, HCO2Et {CHO}, PhCON(OMe)Me

{COPh}, I2 {I}, MeOCOCl {CO2Me}.

Scheme 44 Deprotonative functionalization of 2-methoxyquinoxa-

line. Reaction conditions: [a] LTMP, THF, 270 uC, 2 h; [b] Electrophile

{El}: DCl/EtOD {D}, MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, 2-MeOC6H4CHO {CH(OH)(2-MeOC6H4)}, Ph2CO

{C(OH)Ph2}, I2 {I}; [c] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



2-(methylsulfanyl)quinoxaline (interception of the lithio com-

pound with N-methoxy-N-methylbenzamide in 42% yield).56a

Whereas methylsulfinyl- and methylsulfonylpyrazine were

mainly deprotonated on the methyl group upon treatment with

LTMP, phenylsulfonylpyrazine underwent ring deprotonation

using LDA to give after transformation the 3-substituted

derivative in 33% yield.30 tert-Butylsulfinyl- and tert-butylsul-

fonylpyrazine similarly led to the 3-substituted derivatives 84

in modest yields (Scheme 47).31

4.6 Metalation of N-protected amino- pyrazines and

quinoxalines

The metalation of N-pivaloyl protected aminopyrazine was

unsuccessfully attempted using butyl-, tert-butyl- and mesityl-

lithium due to easier nucleophilic addition. Recourse to LTMP

(2 equiv.) resulted in an incomplete metalation at the

3-position when used in THF at 0 uC, as demonstrated by

quenching with benzaldehyde to give after hydrolysis the

expected alcohol in 25% yield.62 Deprotonation of N-tert-

butoxycarbonyl diprotected 2,5-diaminopyrazine was achieved

using 8 equiv. of the mixed Li–K system obtained by mixing

LTMP and potassium tert-butoxide, after replacement of the

carbamate protons by tributylstannyl groups, as evidenced by

interception with chlorotributylstannane (Scheme 48).61

Subsequent Pd/Cu couplings with diiodopyrazines 82 were

utilized to prepare polymers.

Treatment of N-pivaloyl protected 2-aminoquinoxaline with

LTMP in THF at –70 uC resulted in the regioselective

metalation next to the directing group to afford after trapping

the 3-substituted derivatives 85 (Scheme 49).58

4.7 Metalation of pyrazinecarboxamides and

pyrazinethiocarboxamides

Reactions between N-(tert-butyl)pyrazinecarboxamide and

LTMP were conducted in THF at temperatures between

280 uC and 0 uC prior to deuteriolysis. Whereas mixtures

where the 5-deuterated derivative 86 predominates were

obtained at very low temperatures (45% of 86 against 25% of

87 (El = D) at 280 uC) probably via a kinetic lithio compound

at C5, the 3-deuterated compound 87 (El = D) was detected at

0 uC (4 equiv. of base) as the only product probably via a

thermodynamic lithio compound at C3, stabilized by the

chelating deprotonated carboxamide function. Subsequent

functionalization of the deprotonated site was next considered

(Scheme 50).62

Starting from N-methyl-, N-(tert-butyl)- and N,N-diisopro-

pylpyrazinethiocarboxamide, a complete regioselectivity in

favor of the kinetic 5-lithio intermediate was observed at low

temperature, leading to the compounds 88 (Scheme 51).63

Scheme 45 Deprotonative functionalization of pyrazine-2,5-diketals.

Reaction conditions: [a] LTMP, THF, 225 uC, 4 h; [b] I2; [c] hydrolysis.

Scheme 46 Deprotonative functionalization of methylsulfanyl- and

phenylsulfanylpyrazine. Reaction conditions: [a] LTMP, THF, 275 uC,

20 min; [b] Electrophile {El}: PhCON(OMe)Me {COPh}; [c] hydro-

lysis; [d] LTMP, THF, 275 uC, 1 h; [e] Electrophile {El}: MeCHO

{CH(OH)Me}.

Scheme 47 Deprotonative functionalization of sulfinyl- and sulfo-

nylpyrazine. Reaction conditions: [a] LTMP or LDA, THF, 275 uC, 30

min; [b] Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}, I2 {I}; [c] hydrolysis.

Scheme 48 Deprotonative functionalization of N-tert-butoxycarbo-

nyl diprotected 2,5-diaminopyrazine. Reaction conditions: [a] NaH,

THF, rt, 1 h; [b] Bu3SnCl, rt, 15 min; [c] LTMP, tBuOK, DEE, rt, 3 h;

[d] Bu3SnCl, rt, overnight; [e] hydrolysis.

Scheme 49 Deprotonative functionalization of N-pivaloyl 2-amino-

quinoxaline. Reaction conditions: [a] LTMP, THF, 270 uC, 2.5 h; [b]

Electrophile {El}: MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}, I2

{I}, CO2 {CO2H}; [c] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



5. Conclusions

The methods outlined above allowed the functionalization of

numerous diazines, and hence opened an entry to a great

variety of building blocks, e.g. if combined with other

reactions such as cross-couplings.64

Despite all the applications so far featured, problems

remain. The tendency of the substrates to undergo nucleophilic

additions or substitutions limits the scope of the reaction.

Recourse to LTMP to perform these reactions reduces

nucleophilic attacks of the base to the substrate, but is helpless

to prevent reactions from the lithiated substrate. In addition,

reactions using LTMP are equilibria, and an excess of base is

in general required to ensure satisfying yields.

Recently, new bases such as magnesates and zincates started

to emerge, and proved convenient to allow reactions that were

not accessible using lithium bases. The scope of these bases for

the deprotonation of heterocycles, so far demonstrated with

very sensible substrates such as bare diazines and halo

pyrimidines deserves to be tested further.

References

1 T. Eicher, S. Hauptmann and A. Speicher, The Chemistry ofHeterocycles, 2nd ed., Wiley-VCH, 2003, Chapter 6.

2 (a) M. Tisler and B. Stanovnik, Comprehensive HeterocyclicChemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon Press,Oxford, 1984, Vol. 3, p. 1; (b) W. J. Coates, ComprehensiveHeterocyclic Chemistry, ed. A. R. Katritzky, C. W. Rees andE. F. V. Scriven, Pergamon, Oxford, 2nd edn, 1996, Vol. 6, p. 1.

3 (a) R. A. Carboni and R. V. Lindsey, Jr., J. Am. Chem. Soc., 1959,81, 4342–4346; (b) D. L. Boger, Chem. Rev., 1986, 86, 781–794.

4 A. W. Dox and L. Yoder, J. Am. Chem. Soc., 1922, 44, 361–366.5 P. Molina, A. Arques, V. Vinader, J. Becher and K. Brondum,

Tetrahedron Lett., 1987, 28, 4451–4454.

6 H. Bredereck, R. Gompper and H. Herlinger, Chem. Ber., 1958, 91,2832–2849.

7 (a) G. W. H. Cheeseman and E. S. G. Werstiuk, Advances inHeterocycles Chemistry, Academic Press: New York, 1972, Vol. 14,p. 99; (b) G. B. Barlin, The Chemistry of Heterocyclic Compounds,Wiley, New York, 1982, Vol. 41.

8 G. Buchi and J. Galindo, J. Org. Chem., 1991, 56, 2605–2606.9 C. Najera, J. M. Sansano and M. Yus, Tetrahedron, 2003, 59,

9255–9303.10 K. Shen, Y. Fu, J.-N. Li, L. Liu and Q.-X. Guo, Tetrahedron, 2007,

63, 1568–1576.11 T. Imahori and Y. Kondo, J. Am. Chem. Soc., 2003, 125,

8082–8083.12 (a) G. Queguiner, F. Marsais, V. Snieckus and J. Epsztajn, Adv.

Heterocycl. Chem., 1991, 52, 187–304; (b) F. Mongin andG. Queguiner, Tetrahedron, 2001, 57, 4059–4090; (c) M. Schlosserand F. Mongin, Chem. Soc. Rev., 2007, 36, 1161–1172.

13 (a) A. Turck, N. Ple, F. Mongin and G. Queguiner, Tetrahedron,2001, 57, 4489–4505; (b) A. Godard, A. Turck, N. Ple, F. Marsaisand G. Queguiner, Trends Heterocycl. Chem., 1993, 3, 16–29; (c)A. Turck, N. Ple and G. Queguiner, Heterocycles, 1994, 37,2149–2172.

14 A. J. Clarke, S. McNamara and O. Meth-Cohn, Tetrahedron Lett.,1974, 15, 2373–2376.

15 M. Schlosser, O. Lefebvre and L. Ondi, Eur. J. Org. Chem., 2006,1593–1598.

16 C. Berghian, M. Darabantu, A. Turck and N. Ple, Tetrahedron,2005, 61, 9637–9644.

17 N. Ple, A. Turck, K. Couture and G. Queguiner, J. Org. Chem.,1995, 60, 3781–3786.

18 A. Seggio, F. Chevallier, M. Vaultier and F. Mongin, J. Org.Chem., 2007, 72, 6602–6605.

19 (a) A. Turck, N. Ple, V. Tallon and G. Queguiner, Tetrahedron,1995, 51, 13045–13060; (b) V. Gautheron-Chapoulaud, N. Ple andG. Queguiner, Tetrahedron, 2000, 56, 5499–5507.

20 L. Decrane, N. Ple and A. Turck, J. Heterocycl. Chem., 2005, 42,509–513.

21 A. Turck, N. Ple, L. Mojovic and G. Queguiner, J. Heterocycl.Chem., 1990, 27, 1377–1381.

22 F. Toudic, A. Turck, N. Ple, G. Queguiner, M. Darabantu,T. Lequeux and J. C. Pommelet, J. Heterocycl. Chem., 2003, 40,855–860.

23 A. Turck, N. Ple, B. Ndzi, G. Queguiner, N. Haider, H. Schullerand G. Heinisch, Tetrahedron, 1993, 49, 599–606.

24 A. Turck, N. Ple, L. Mojovic and G. Queguiner, Bull. Soc. Chim.Fr., 1993, 130, 488–492.

25 (a) L. Mojovic, A. Turck, N. Ple, M. Dorsy, B. Ndzi andG. Queguiner, Tetrahedron, 1996, 52, 10417–10426; (b) N. Ple,A. Turck, K. Couture and G. Queguiner, Synthesis, 1996,838–842.

26 F. Trecourt, A. Turck, N. Ple, A. Paris and G. Queguiner,J. Heterocycl. Chem., 1995, 32, 1057–1062.

27 V. Gautheron-Chapoulaud, I. Salliot, N. Ple, A. Turck andG. Queguiner, Tetrahedron, 1999, 55, 5389–5404.

28 (a) R. J. Mattson and C. P. Sloan, J. Org. Chem., 1990, 55,3410–3412; (b) J. J. Lee and S. H. Cho, Bull. Korean Chem. Soc.,1996, 17, 868–869, (Chem. Abstr., 1996, 125, 300930h).

29 A. Turck, N. Ple, A. Lepretre-Gaquere and G. Queguiner,Heterocycles, 1998, 49, 205–214.

30 A. Turck, N. Ple, P. Pollet, L. Mojovic, J. Duflos andG. Queguiner, J. Heterocycl. Chem., 1997, 34, 621–627.

31 A. Turck, N. Ple, P. Pollet and G. Queguiner, J. Heterocycl. Chem.,1998, 35, 429–436.

32 P. Pollet, A. Turck, N. Ple and G. Queguiner, J. Org. Chem., 1999,64, 4512–4515.

33 N. Le Fur, L. Mojovic, N. Ple, A. Turck, V. Reboul andP. Metzner, J. Org. Chem., 2006, 71, 2609–2616.

34 N. Le Fur, L. Mojovic, N. Ple, A. Turck and F. Marsais,Tetrahedron, 2005, 61, 8924–8931.

35 A. Turck, N. Ple, L. Mojovic, B. Ndzi, G. Queguiner, N. Haider,H. Schuller and G. Heinisch, J. Heterocycl. Chem., 1995, 32,841–846.

36 C. Fruit, A. Turck, N. Ple, L. Mojovic and G. Queguiner,Tetrahedron, 2002, 58, 2743–2753.

Scheme 51 Deprotonative functionalization of N-methyl-, N-(tert-

butyl)- and N,N-diisopropylpyrazinethiocarboxamide. Reaction condi-

tions: [a] LTMP, THF, 275 uC, 1.5 h; [b] Electrophile {El}: DCl/EtOD

{D}, MeCHO {CH(OH)Me}, PhCHO {CH(OH)Ph}, Ph2CO

{C(OH)Ph2}, C2Cl6 {Cl}, Bu3SnCl {SnBu3}, MeI {Me}, Me3SiCl

{SiMe3}, I2 {I}, (PhS)2 {SPh}; [c] hydrolysis.

Scheme 50 Deprotonative functionalization of N-(tert-butyl)pyrazi-

necarboxamide. Reaction conditions: [a] LTMP, THF, 0 uC, 1 h; [b]

Electrophile {El}: DCl/EtOD {D}, MeCHO {CH(OH)Me}, PhCHO

{CH(OH)Ph}; [c] hydrolysis.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



37 A. Krasovskiy, V. Krasovskaya and P. Knochel, Angew. Chem.,2006, 118, 3024–3027, (Angew. Chem., Int. Ed., 2006, 45,2958–2961).

38 (a) A. Busch, V. Gautheron-Chapoulaud, J. Audoux, N. Ple andA. Turck, Tetrahedron, 2004, 60, 5373–5382; (b) N. Le Fur,L. Mojovic, A. Turck, N. Ple, G. Queguiner, V. Reboul, S. Perrioand P. Metzner, Tetrahedron, 2004, 60, 7983–7994.

39 T. J. Kress, J. Org. Chem., 1979, 44, 2081–2082.40 (a) R. Radinov, M. Haimova and E. Simova, Synthesis, 1986,

886–891; (b) R. Radinov, C. Chanev and M. Haimova, J. Org.Chem., 1991, 56, 4793–4796.

41 N. Ple, A. Turck, P. Martin, S. Barbey and G. Queguiner,Tetrahedron Lett., 1993, 34, 1605–1608.

42 N. Ple, A. Turck, E. Fiquet and G. Queguiner, J. Heterocycl.Chem., 1991, 28, 283–287.

43 (a) C. Parkanyi, N. S. Cho and G. S. Yoo, J. Organomet. Chem.,1988, 342, 1–7; (b) M. Cushman, J. T. Mihalic, K. Kis andA. Bacher, J. Org. Chem., 1999, 64, 3838–3845.

44 N. Ple, A. Turck, A. Heynderickx and G. Queguiner, J. Heterocycl.Chem., 1994, 31, 1311–1315.

45 N. Ple, A. Turck, A. Heynderickx and G. Queguiner, J. Heterocycl.Chem., 1997, 34, 551–556.

46 N. Ple, A. Turck, A. Heynderickx and G. Queguiner, Tetrahedron,1998, 54, 9701–9710.

47 (a) A. Wada, J. Yamamoto and S. Kanatomo, Heterocycles, 1987,26, 585–589; (b) A. Wada, J. Yamamoto, Y. Hamaoka, K. Ohki,S. Nagai and S. Kanatomo, J. Heterocycl. Chem., 1990, 27,1831–1835.

48 (a) N. Ple, A. Turck, F. Bardin and G. Queguiner, J. Heterocycl.Chem., 1992, 29, 467–470; (b) N. Ple, A. Turck, K. Couture andG. Queguiner, Tetrahedron, 1994, 50, 10299–10308.

49 W. Schwaiger and J. P. Ward, Recl. Trav. Chim. Pays-Bas, 1971,90, 513–515.

50 G. P. Rizzi, J. Org. Chem., 1974, 39, 3598.

51 (a) C. Fruit, A. Turck, N. Ple, L. Mojovic and G. Queguiner,Tetrahedron, 2001, 57, 9429–9435; (b) F. Toudic, N. Ple, A. Turckand G. Queguiner, Tetrahedron, 2002, 58, 283–293.

52 F. Buron, N. Ple, A. Turck and G. Queguiner, J. Org. Chem., 2005,70, 2616–2621.

53 F. Toudic, A. Heynderickx, N. Ple, A. Turck and G. Queguiner,Tetrahedron, 2003, 59, 6375–6384.

54 Y. Aoyagi, A. Maeda, M. Inoue, M. Shiraishi, Y. Sakakibara,Y. Fukui, A. Ohta, K. Kajii and Y. Kodama, Heterocycles, 1991,32, 735–748.

55 (a) A. Turck, L. Mojovic and G. Queguiner, Synthesis, 1988,881–884; (b) A. Turck, N. Ple, D. Dognon, C. Harmoy andG. Queguiner, J. Heterocycl. Chem., 1994, 31, 1449–1453; (c)W. Liu, J. A. Walker, J. J. Chen, D. S. Wise and B. L. Townsend,Tetrahedron Lett., 1996, 37, 5325–5328.

56 (a) J. S. Ward and L. Merritt, J. Heterocycl. Chem., 1991, 28,765–768; (b) A. Turck, D. Trohay, L. Mojovic, N. Ple andG. Queguiner, J. Organomet. Chem., 1991, 412, 301–310.

57 W. Liu, D. S. Wise and L. B. Townsend, J. Org. Chem., 2001, 66,4783–4786.

58 A. Turck, N. Ple, V. Tallon and G. Queguiner, J. Heterocycl.Chem., 1993, 30, 1491–1496.

59 N. Ple, A. Turck, A. Heynderickx and G. Queguiner, Tetrahedron,1998, 54, 4899–4912.

60 C. Berghian, E. Condamine, N. Ple, A. Turck, I. Silaghi-Dumitrescu, C. Maiereanu and M. Darabantu, Tetrahedron,2006, 62, 7339–7354.

61 C. Y. Zhang and J. M. Tour, J. Am. Chem. Soc., 1999, 121,8783–8790.

62 A. Turck, N. Ple, D. Trohay, B. Ndzi and G. Queguiner,J. Heterocycl. Chem., 1992, 29, 699–702.

63 C. Fruit, A. Turck, N. Ple and G. Queguiner, Heterocycles, 1999,51, 2349–2365.

64 R. Chinchilla, C. Najera and M. Yus, Chem. Rev., 2004, 104,2667–2722.


Publ

ishe

d on

20

Nov

embe

r 20

07. D

ownl

oade

d by

ET

H-Z

uric

h on

07/

09/2

015

12:0

5:03



Documents

Functionalization of diazines and benzo derivatives ...szolcsanyi/education/files/Chemia... · Functionalization of diazines and benzo derivatives through deprotonated intermediates